Expression of Disialoganglioside (GD2) in Neuroblastic Tumors: A Prognostic Value for Patients Treated With Anti-GD2 Immunotherapy

Abstract

Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is one of the most aggressive pediatric cancers. Patients with stage IV high-risk neuroblastoma receive an intensive multimodal therapy ending with an immunotherapy based on a chimeric monoclonal antibody ch14.18. Although the use of ch14.18 monoclonal antibody has significantly increased the survival rate of high-risk neuroblastoma patients, about 33% of these patients still relapse and die from their disease. Ch14.18 targets the disialoganglioside, GD2, expressed on neuroblastic tumor (NT) cells. To better understand the causes of tumor relapse following ch14.18 immunotherapy, we have analyzed the expression of GD2 in 152 tumor samples from patients with NTs using immunohistochemical stainings. We observed GD2 expression in 146 of 152 samples (96%); however, the proportion of GD2-positive cells varied among samples. Interestingly, low percentage of GD2-positive cells before immunotherapy was associated with relapse in patients receiving ch14.18 immunotherapy. In addition, we demonstrated in vitro that the sensitivity of neuroblastoma cell lines to natural killer-mediated lysis was dependent on the proportion of GD2-positive cells, in the presence of ch14.18 antibody. In conclusion, our results indicate that the proportion of tumor cells expressing GD2 in NTs should be taken in consideration, as a prognostic marker, for high-risk neuroblastoma patients receiving anti-GD2 immunotherapy.

Positron Emission Tomography Detects In Vivo Expression of Disialoganglioside GD2 in Mouse Models of Primary and Metastatic Osteosarcoma

“…Building on the therapeutic success of recent clinical trials of GD2-targeted immunotherapy in neuroblastoma (11,49), there is strong clinical interest in treatment protocols that include anti-GD2 immunotherapy for other malignancies, such as osteosarcoma, where GD2 expression is lower and/or less uniform than in neuroblastoma (17). Current in vitro methods for measuring GD2 expression (IHC, quantitative PCR and flow cytometry) are highly dependent on factors such as tumor sampling, tissue processing, and operator interpretation, which could explain inconsistencies in reported GD2 levels (19,20,22). A PETbased assay of GD2 expression enables quantitative in situ interrogation of the entire tumor volume and allows surveillance of changes in all disease sites throughout the body.…”

“…Although GD2 is nearly ubiquitous in osteosarcoma (2,3) and neuroblastoma (6,7), its expression level is highly variable (3,12,(18)(19)(20). Terzic and colleagues demonstrated a correlation between the variability in GD2 expression and response to ch14.18 treatment in neuroblastoma (20), leading researchers to hypothesize that differences in GD2 expression, both between patients and within a given tumor, may contribute to variations in immunotherapy response (21).…”

“…One study reported higher GD2 expression in recurrent osteosarcomas compared with initial biopsy (3), whereas another observed no difference between primary and recurrent osteosarcoma sites (19). One reason for this discordance may be that current in vitro GD2 assays are highly dependent on tumor sampling (19,20), tissue processing (the gangliosides are soluble in some solvents used to fix tissue; ref. 22), and operator interpretation.…”

Don’t sugarcoat it: How glycocalyx composition influences cancer progression

“…Furthermore, the GD3 structure has been shown to bind and suppress both T helper and NKT cell function in brain and ovarian cancers (Mycko et al, 2014; Webb et al, 2012). GD2 is also a well-known ganglioside that is up-regulated in in melanoma, lung cancers, sarcomas, neuroblastomas, and triple-negative breast cancers (Dobrenkov et al, 2016; Orsi et al, 2017; Terzic et al, 2018; Yanagisawa et al, 2011). GD2 associates with the VLA-2 integrin and up-regulates the binding of neuroblastomas to ECM proteins such as collagens.…”

The first experience of using immunotherapy in a patient with a recurrence of neuroblastoma

“…С помощью динутуксимаба происходит лучшее распознавание опухоли иммунной системой хозяина, что запускает клеточно-опосредованную цитотоксичность. По данным зарубежных исследований, применение ИТ позволяет повысить бессобытийную выживаемость до 60 % [2][3][4][5][6].…”